Pathway-focused genetic evaluation of immune and inflammation related genes with CFS

[knackers323]

Umm:

rs4151667 - TT
rs1061170 - CT

I don't appear to have data for rs11214105.



....but....but... darn it!

-J

@JaimeS my results are exactly the same. don't have the rs11214105 result either. how many other people have you run into with these results?

 

[Valentijn]

Most people are TT for rs4151667 - 94%. So I would be expected that many people here are TT for it.

CT for rs1061170 is also extremely common, being present in about 50% of the population.

 

[Valentijn]

I'd forgotten about this paper, but ended up looking into the complement system due to finding a ton of uncommon pathogenic mutations in the ME/CFS patients I have 23andMe data for. Basically we're putting together a new improved version of Analyze My Genes which now tags missense mutations and clinsig data, which includes flags such as "benign", "pathogenic", etc, and makes it easier to look for pathogenic missense mutations which are potentially compound heterozygous.

Anyhow, we're not getting a lot of pathogenic results on any particular SNP or gene, but overall we're getting quite a lot on the genes involved in the innate immune system, whereas our ethnically-matched controls have almost none. Also, the mutations turning up seem to be mostly or entirely down-regulations, resulting in diminished immune responses, primarily to various types of bacteria depending on the specific gene the mutation is on.

Most of these mutations aren't super rare. So far they're between 0.2% and about 6% prevalence in the general population. The genes I've had popping up so far are: C2, C3, C6, C7, ITGB2, FCN2, FCN3, MASP2, TLR4, CLEC7A, TIRAP, and CX3CR1. I'm going to look into them more to see if they're all resulting in some level of deficiency (instead of being up-regulations), and see if any more turn up.

 

[lansbergen]

I'm going to look into them more to see if they're all resulting in some level of deficiency (instead of being up-regulations), and see if any more turn up.

Do you have data to check how many in one person are nvolved?

 

[Valentijn]

Do you have data to check how many in one person are nvolved?

Yes, for the people who I have 23andMe data, I can see if they have multiple pathological mutations. But 23andMe data only includes some of those mutations. Whole Exome Sequencing or sequencing the specific genes involved would be necessary to see all potential mutations.

 

[msf]

´Ethnically matched controls´ - is that like an sick old white British guy with a healthy young Filipina?

 

[Valentijn]

´Ethnically matched controls´ - is that like an sick old white British guy with a healthy young Filipina?

No, the controls are people with the same or very similar maternal haplogroup, and gender is also the same of course. Since genetics have evolved somewhat based on geographic delineations, using ethnically matched controls is a way to avoid getting rare results which are actually quite common for everyone with roots in the same region. Then haplogroups can still be separately considered regarding whether or not they are too prevalent from a bunch of patients on a primarily English-language forum.

If you have a better method to suggest, I'd love to hear it.

 

[msf]

Sorry, that was a silly joke.

Sounds good to me, but isn´t there anything more precise than maternal haplogroup? I know that some haplogroups are spread right across Europe and the Middle East.

 

[Valentijn]

Sounds good to me, but isn´t there anything more precise than maternal haplogroup? I know that some haplogroups are spread right across Europe and the Middle East.

Haplogroups can be very precise. "H1" for example, is pretty vague, but it also includes up to 9 layers of subgroups, which can get very specific to a region. And those broader groups cover a lot of ground because the people in those areas (including both Europe and the Middle East) have the same relatively recent origins.

As an example, http://dna.jameslick.com/mthap/ can use 23andMe to determine maternal haplogroup. For a few that doesn't get any more specific than "H1" or even just "H". But most of us have more detailed results, which are much more geopraphically specific, like H1b1, or even H13a1a1.

The only big problem with this is that it is only tracing back to a single ancestor out of hundreds, on the completely maternal line. So that one maternal ancestor might come from one region, while the rest of someone's ancestors come from elsewhere.

I doubt there is a more precise method, though I could add paternal haplogroup for the males. But that cannot be determined for females, since they lack the highly preserved Y chromosome.

 

[msf]

Yes, I meant to ask whether you were using subgroups, but I´d forgotten the word. I guess there aren´t any better methods than mitochondrial and Y chromosone DNA at the moment, or at least none that are available commercially.